Part 2 Department of Obstetrics and Gynecology University

(Part 2) Department of Obstetrics and Gynecology, University of Oklahoma, 2018 Presented by: Dr Batoul Birjandi

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

pregestation Assess Glucose control Hb. A 1 c<7 Hb. A 1 c≥ 7 No hypoglycemia Recurrent hypoglycemia Con current treatment Adj dose with advancing gestation Increase G. monitoring frequency Target Hb. A 1 c<6% Target Hb. A 1 c<7% Recurrent hypoglycemia Adj treatment No hypoglycemia Adj treatment Increase G. monitoring frequency Target Hb. A 1 c<7% Target Hb. A 1 c<6% No improvement Consider CGM Hypoglycemia resolved Not resolved Consider CGM Consider CSII Hypoglycemia resolved Hb. A 1 c<7% Not Resolved Hb. A 1 c≥ 7 Hypoglycemia resolved Hb. A 1 c≥ 7 Consider CSII

GDM Gestational weight gain monitoring Lifestyle modification Antenatal surviellance Home glucose monitoring Glucose within goals Glucose exceeding goals continue Lifestyle modification Start drug thrapy Review home glucose weekly Glucose within goals Con current treatment Glucose exceeding goals Adj treatment

§ Pregnant women aged 18– 40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy § 325 Participants were pregnant (≤ 13 weeks and 6 days’ gestation) or planning pregnancy from 31 hospitals § participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone

Interpretation : Ø Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. Ø CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy.

§ 300 pregnant women with type 1 diabetes, or type 2 diabetes on insulin therapy with gestational age <16 weeks, or insulin treated GDM with gestational age <30 weeks(2011 -2015) § Primary outcome was macrosomia, defined as birth weight above the 90 th percentile. Secondary outcomes were glycaemic control, maternal and neonatal complications.

Conclusions Ø In diabetic pregnancy, intermittent retrospective CGM use did not reduce the risk of macrosomia. Ø CGM use provides detailed information about glycaemic fluctuations but as a treatment strategy does not translate into improved pregnancy outcome.

flash glucose monitoring (FGM) users can obtain glucose measurements instantly by scanning the glucose sensor with the reader, producing real time data

Conclusion: Good agreement was demonstrated between the Free. Style Libre System and SMBG.

§ Retrospective cohort study § 1, 344 women with GDM § Delivered between 2009 - 2012 § Demographic data, blood sugar values, gestational weight gain, and maternal and neonatal outcome data were abstracted from the medical record and compared among normal-weight, overweight, and obese women.

CONCLUSIONS: Ø Obese women with GDM represent a large, uniquely high-risk population, and ongoing efforts are needed to prevent the development of GDM in these women. Ø more aggressive treatment protocols among obese women with GDM can reduce the risk for adverse outcomes.

• 12 observational studies(between 1975 and 2008 ) • 255 pregnant women with normal weight and glucose tolerance • Glycemic Patterns : hospital admission with frequent blood sampling, SMBG, CGMS.

The current therapeutic targets : ≤ 95 mg/d. L for FBG, 140 mg/d. L for 1 -h PP glucose, and 120 mg/d. L for 2 -h. PP glucose

CONCLUSIONS: The results of 45 years of data characterizing glycemia in normal pregnancy strongly support the need for future prospective studies that specifically test lower therapeutic PP glycemic targets for gestational diabetes, and possibly obese patients, to potentially limit a looming epidemic of fetal macrosomia.

This is the basis for ongoing studies such as the GDM-MOMS study, which is randomizing overweight and obese women with gestational diabetes to either standard glycemic targets (fasting <95 mg/d. L (5. 3 mmol/L), one hour postprandial <140 mg/d. L (7. 8 mmol/L)) or more intensive glycemic control (fasting <90 mg/d. L (5 mmol/L), one hour postprandial <120 mg/d. L (6. 9 mmol/L))

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

Copenhagen, Denmark § Retrospective study of singleton pregnancies from 2007 to 2011 in women with type 1 diabetes with a single living fetus at 22 weeks using either insulin detemir (n = 67) or glargine (n = 46) from conception.

Conclusion Glycaemic control and pregnancy outcome were comparable in women using insulin detemir or glargine with a low rate of severe complications. However, a lower prevalence of large for gestational age infants in women on glargine was seen. Ø The increasing use of both long-acting insulin analogues during pregnancy seems safe. Ø

§ 56 women with pregestational and 82 with gestational diabetes

*cranial (CC) and thoracic circumferences (TC) CC/TC < 1 : indicates a disproportional body composition

§ Adverse outcomes for both the mother and the newborn were less frequently found in pregnant women with any type of diabetes treated with glargine when compared with those treated with NPH insulin. § We propose that women with pregestational diabetes may remain on glargine throughout their pregnancy if they are already using it; those with gestational diabetes can also start its use, from diagnosis onwards. Insulin glargine may be considered a new tool and alternative long-acting insulin for the treatment of diabetes in pregnancy.

§ systematic review § Medline, Embase, and the Cochrane Central Register of Controlled Trials through May 2013 § comparing CSII with MDI in pregnant women with diabetes mellitus

Combined relative risk of maternal outcomes in MDI versus CSII interventions among pregnant women with preexisting type 1 diabetes. (a) Combined relative risk of cesarean delivery in MDI versus CSII interventions among pregnant women with preexisting type 1 diabetes. (b) Combined relative risk of severe maternal hypoglycemia in MDI versus CSII interventions among pregnant women with preexisting type 1 diabetes.

Combined relative risk of neonatal outcomes in MDI versus CSII interventions among pregnant women with preexisting type 1 diabetes. (a) Combined relative risk of neonatal hypoglycemia comparing CSII with MDI among pregnant women with preexisting diabetes. (b) Combined mean betweengroup difference between MDI and CSII in birth weight among infants born to women with preexisting type 1 diabetes.

(c) Combined relative risk of major congenital anomalies in MDI versus CSII interventions among infants born to women with preexisting type 1 diabetes. (d). Combined relative risk of neonatal intensive care unit admission in MDI versus CSII interventions among infants born to women with preexisting type 1 diabetes. (e) Combined relative risk of preterm delivery in MDI versus CSII interventions among pregnant women with preexisting type 1 diabetes.

Conclusion similar improvements in Hb. A 1 c with CSII and MDI during pregnancy, but evidence was insufficient to rule out possible important differences between CSII and MDI for maternal and fetal outcomes.

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

§ 16 study (n = 2165) § Eligible studies were randomized control trials (RCTs) or follow-up of an RCT that: § (1) compared metformin with insulin in pregnancy in women with gestational diabetes mellitus or Type 2 diabetes; and § (2) reported maternal or fetal outcomes of interest

Conclusions Metformin had no short-term adverse effects on pregnancy

§ Randomized, open label study § 206 patients( type 2 diabetes) § Insulin was added to metformin treatment when required, to maintain the target glycemic control

Conclusion § Metformin is an effective treatment option for women with type 2 diabetes in pregnancy with or without add-on insulin. § Metformin has advantages over insulin such as less maternal weight gain, no maternal hypoglycemia, being cheap, being oral therapy, and requiring no vigorous monitoring and frequent hospital admissions with good compliance and acceptability. § Metformin treatment when compared with insulin treatment showed less maternal hypertensive complications and less risk of neonatal hypoglycemia with few neonatal intensive care admissions. § Metformin treatment is suitable for non obese type 2 diabetes patients in pregnancy without complications. § Metformin treatment in type 2 diabetes in pregnancy required lower dose of add-on insulin, at a later gestational age for maintaining glycemic control when compared with insulin treatment.

§ RCT § Routine visits to child welfare clinics at the ages of 6, 12, and 18 months, including weight and height measurements, and assessment of motor, social, and linguistic development. § Sample: The children of mothers with GDM randomized to metformin (n = 47) or insulin (n = 50) treatment during pregnancy.

Conclusion: Ø The study found no adverse influence of prenatal metformin exposure on motor, linguistic, or social development of the offspring during the first 18 months of life, as compared with insulin exposure. Ø The relevance of the finding that infants exposed to metformin were heavier at the age of 12 months and both taller and heavier at 18 months needs to be settled in long-term studies.

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

JAMA Pediatr. 2015 § Retrospective cohort study of a population-based cohort from a nationwide US employer-based insurance claims database from January 1, 2000, to December 31, 2011 § Among 110 879 women with GDM, 9173 women (8. 3%) were treated with glyburide (n = 4982) or insulin (n = 4191)

NICU RDS Hypoglycemia Jaundice Macrosomia

Conclusions Ø There is association between glyburide (compared with insulin) and elevated risk of NICU admission, neonatal hypoglycemia, respiratory distress, birth injury, and large for gestational age in women with GDM.

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

© 2017 by the American Diabetes Association. § prospective randomized controlled study § GDM at 13– 33 weeks gestation § Glyburide in 53 patients and metformin in 51.

CONCLUSIONS: In this randomized controlled trial, both treatments were similar in their efficacy and safety.

Agenda • Introduction • Cares (Preconception/during pregnancy/ post partum) • Insulin • Metformin • Glyburide versus metformin • Alternate oral agents • Conclusions

Obstetrics Department, Federal University of Sa˜ o Paulo, Brazil § RCT § To compare neonatal results from patients with gestational diabetes mellitus (GDM) who were treated with insulin, glyburide and acarbose. § 3 groups: insulin therapy (ns 27), glyburide therapy (ns 24) and acarbose therapy (ns 19).

In our study, changing therapy to insulin was required in 8 patients using acarbose (42. 1%) and in only 5 patients from the glyburide (20. 8%) group, thus corroborating the view that acarbose is less effective than glyburide for glycemic control.

Conclusion: We believe that glyburide and acarbose can be promising alternative therapies for the treatment of GDM. Glyburide controlled glucose levels in most patients and it was more efficient than acarbose. § Glyburide showed a higher rate of macrosomia and neonatal hypoglycemia as compared to otherapies. §

Guidelines

Conclusions • Target Hb. A 1 c<6% • CGM ? • FGM • Obese women with GDM represent a large, uniquely high-risk population • Insulin glargine • CSII: insufficient evidenve to rule out possible important differences • Metformin • Glyburide/Acarbose